Imidazole derivatives, preparation and therapeutic application thereof

ABSTRACT

A compound of formula (I)the process of preparing compounds of formula (I), their pharmaceutical compositions, and the method of treating diseases associated with M3 muscarinic and/or S-HT4 serotoninergic receptors.

This application is a 371 of PCT/FR98/02446 filed Nov. 17, 1998.

The subject of the present invention is imidazole derivatives of generalformula (I)

in which:

A represents a saturated or unsaturated heterocycle comprising anitrogen atom of formula (B), (D), (E) or (F):

R₁ and R₂ represent, independently of each other, a hydrogen, a C₁₋₆alkyl group, or together form a polymethylene group —(CH₂)_(n)—, itbeing possible for n to take the values from 3 to 6,

R₅ represents a phenyl or a 2-, 3- or 4-pyridine, the phenyl or thepyridine being substituted with R₃ and R′₃,

where R₃ and R′₃ represent, independently of each other, a hydrogenatom, a halogen atom, a hydroxyl, a C₁₋₄ alkyl or C₁₋₆ alkoxy group,

R₆ represents a phenyl or a 2-, 3- or 4-pyridine, the phenyl or thepyridine being substituted with R₄ and R′₄,

where R₄ and R′₄ represent, independently of each other, a hydrogenatom, a halogen atom, a hydroxyl, an amino, a cyano, a sulphonamide, anaminocarbonyl, a trifluoromethyl, a C₁₋₆-alkoxy, (di)hydroxy-C₁₋₆ alkoxyor C₁₋₄ alkyl group, and

R₇ represents a hydrogen atom or a C₁₋₂ alkyl group.

Among these, the preferred compounds according to the invention are thecompounds for which: A represents a piperidine (B), more especially Arepresents a piperidine (B) and R₅ represents a phenyl.

Among the latter, the compounds for which R₆ also represents a phenyland R₇ represents a hydrogen are even more particularly preferred.

Within the framework of the present invention, there is understood by:

C_(1-z), where z may take the values between 2 and 6, a carbon chainwhich may have from 1 to z carbon atoms,

alkyl, a linear or branched saturated aliphatic group; for example, aC₁₋₆ alkyl group represents a linear or branched carbon chain of 1 to 6carbon atoms, or preferably of 1 to 6, and more particularly consists ofa methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and thelike;

alkoxy, an alkyloxy group with a linear or branched saturated aliphaticchain, and

halogen atom, a fluorine, a chlorine, a bromine or an iodine.

The compounds of general formula (I) may exist in the form of a freebase, N-oxide or of addition salts with pharmaceutically acceptableacids, which also form part of the invention.

The compounds of general formula (I) comprise one or more asymmetriccarbon atoms. They may therefore is exist in the form of enantiomers ordiastereoisomers. These enantiomers, diastereoisomers, as well asmixtures thereof, including the racemic mixtures, form part of theinvention.

The compounds of the invention can be prepared by processes illustratedin the schemes which follow, for which the operating conditions areroutine for persons skilled in the art.

An epoxide of formula (II) is reacted successively with triflic acid indimethyl sulphoxide and then with diisopropylethylamine to give thehydroxyketone (III) according to the method described by B. M. Trost inTetrahedron letters 29, (18) 2163-66 (1988).

The hydroxyketone (III) is reacted with an arylurea (R₅NHCONH₂) at 180°C. in hexanol, optionally in the presence of a molecular sieve, to givethe imidazolone (IV).

This imidazolone (IV) can also be obtained from the alpha-haloketone(V), by successive reactions of potassium phthalimide (PhthalK) and thenof concentrated hydrobromic acid and of acetic acid, to give, first ofall, the hydrobromide of the aminoketone (VI) which, by treatment with aphenylisocyanate (R₅NCO) in pyridine or dimethylformamide, gives thecompound (IV).

Alternatively, the imidazolone (IV) may be prepared as indicated inScheme 2 according to the method described in U.S. Pat. No. 3,432,520.

A propargylamine of formula (XV), in which R₁ is as defined above andR′₂ represents R₂ minus a carbon atom (R₂═R′₂—(C≡)—), is reacted with aphenylisocyanate (R₅—NCO) in toluene to give the urea (XVI) which, bytreatment with an alkali metal alcoholate, such as sodium methoxide orethoxide or potassium tert-butoxide, in the corresponding alcohol,causes an allenic rearrangement followed by cyclization to give theimidazolone (IV).

The imidazolone (IV) is then heated at the reflux temperature ofphosphorus oxichloride, optionally in the presence of phosphoruspentachloride or of gaseous hydrochloric acid, to give thechloroimidazole (VII).

The condensation of the chloroimidazole (VII) with an alcohol of formula(XIV), in which A, R₆ and R₇ are as defined above, is carried out by theprior action of a non-nucleophilic base such as sodium hydride on thisalcohol, followed by the reaction with the chloroimidazole indimethylformamide at temperatures of between 20 and 120° C. (oil bath ormicrowave oven) to give the compounds of formula (I).

Alternatively, the compounds of formula (I) may be obtained from analpha-haloketone of formula (V) which is thermally condensed withformamide to give the imidazole (VIII).

This imidazole (VIII) is then subjected to the action of atriarylbismuth ((R₅)₃Bi) in the presence of copper acetate and oftriethylamine in dichloromethane to give the imidazole (IX).

The proton at the 2-position of this imidazole (IX) is then removed bymeans of butyllithium in tetrahydrofuran at temperatures of between −78and −10° C. The anion thus formed is trapped by means of dimethyldisulphide to give the sulphide (X).

Alternatively, the sulphides of formula (X) and more particularly thosefor which R₂ is a hydrogen atom may be obtained according to the Scheme3.

The isothiocyanate of formula (XVIII) is brought into contact, in anorganic solvent such as toluene or dichloromethane, with a dialkylacetal of formula (XIX) to give, in an intermediate phase, a thioureawhich is cyclized into an imidazolinethione of formula (XX) by heatingin an aqueous solution (0.01 to 12 N) of hydrochloric acid. Theimidazolinethione of formula (XX) may be S-methylated by the successiveaction of sodium hydride and of methyl iodide in dimethylformamide attemperatures of between −20° C. and 60° C., to give the compound offormula (X), or alternatively by the action of methanol in hydrochloricacid at temperatures of between 20° C. and the reflux temperature.

The sulphide (X) is oxidized into a sulphone (XI) by the action ofOxone® (potassium peroxymonosulphate) in the presence of moist alumina.However, other oxidizing agents may be used, such as hydrogen peroxideor potassium permanganate in acetic acid.

The condensation of the sulphone (XI) with an alcoholate, formed by theaction of a non-nucleophilic base such as sodium hydride on the alcoholof formula (XIV), is carried out in dimethylformamide at temperatures ofbetween 20 and 120° C., to give the compounds of formula (I).

Alternatively, the compounds of formula (I), in which R₆ is a phenyl,R₄═H and R′₄═H, can be modified in order to give other derivatives offormula (I) as indicated in Scheme 4.

The compounds of formula (I), in which R₆ represents a phenyl, R₄ andR′₄═H are debenzylated by the action of ammonium formate at the refluxtemperature of methanol in the presence of a catalytic quantity ofpalladium on carbon, to give the derivative (XII).

The compounds of formula (XII) may then be reacted with an aryl halideof formula (XVII, R₆=phenyl or pyridyl in which R₄ and R′₄ may bedifferent from a halogen) in the presence of a proton-accepting amine orof an inorganic base such as potassium carbonate, or by reductiveamination by means of an aldehyde of formula (XXI, R₆ being as definedabove) in the presence of hydrochloric acid or of sodiumcyanoborohydride in methanol, to give the compounds of formula (I), inwhich R₄ and/or R′₄ do not represent a hydrogen.

In the case where (R₄ and/or R′₄) and/or (R₃ and/or R′₃) is aderivatizable functional group, it may be optionally oxidized, reduced,alkylated or dealkylated by conventional methods known to personsskilled in the art.

The compounds of formula (XIV) are commercially available or may besynthesized according to methods known to persons skilled in the art.

For example, the compound of formula (XIV), in which A represents apiperidine, and R₆ and R₇ are as defined above, may be obtainedaccording to Scheme 5.

Ethyl isonipecotate is alkylated with the compound of formula (XVII), asdefined above, to give the ester (XIII) which is reduced with the mixedhydride of lithium and aluminium to give the alcohol (XIV), according tomethods known to persons skilled in the art. According to anotherexample, the compound of formula (XIV), in which A represents anunsaturated heterocycle of formula (D), and R₆ and R₇ are as definedabove, may be obtained according to Scheme 6.

According to this scheme, 4-pyridinemethanol is reacted with the halideof formula (XVII), in toluene under reflux. The compound of formula(XXII) thus obtained is then reduced, in the presence for example ofsodium borohydride in ethanol, to give the compound (XIV).

The compounds of formula (XIV), in which A represents a heterocycle offormula (E) or (F), and R₆ and R₇ are as defined above, may be obtainedaccording to the method described by W. Schneider (Ger. Arch. Pharm.,308(5), 365-75 (1975)).

The other raw materials are directly available commercially, aredescribed in the literature or can be synthesized by conventionalmethods known to persons skilled in the art.

The following examples illustrate the processes and techniques used forthe preparation of this invention, without however limiting the scope ofthe invention. The elemental microanalysis and the NMR and IR spectraconfirm the structures of the compounds obtained.

EXAMPLE 1 2-hydroxycyclohexanone

9.8 g (0.1 mol) of cyclohexene oxide in 75 ml of dimethyl sulphoxide arecooled on an ice bath, and a solution of 9 ml (0.1 mol) of triflic acidin 25 ml of dimethyl sulphoxide is added over 30 minutes. The mixture isallowed to return to room temperature and stirred for a further 2 hours.150 ml of dichloromethane are added, the mixture is cooled to −78° C.and 87 ml (0.5 mol) of diisopropylethylamine are added over 30 minutes.The mixture is allowed to return to room temperature, stirred for afurther 1 hour and poured over 1500 ml of a 10% solution of sodiumbisulphate. The mixture is extracted with dichloromethane, dried overMgSO₄ and then evaporated. The residual oil is purified by flashchromatography on silica, eluting with methylene chloride, and 4.5 g ofproduct are recovered. Yield=39.5%.

EXAMPLE 2 1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazol-2-one

A mixture of 4.5 g (39.4 mmol) of 2-hydroxycyclohexanone, 7.5 g (55mmol) of phenylurea and 7 ml of hexanol is stirred under reflux for 20hours. The mixture is concentrated under vacuum and the solid residue isrecrystallized from acetone, and 2.5 g of product, m.p.=220° C., arerecovered. Yield—29.6%.

EXAMPLE 3 2-aminocyclohexanone hydrobromide

Following the procedure of D. Y. Curtin (J.Am. Chem. Soc. 77, 1105-10(1955)), a mixture of 50 g (0.27 mol) of potassium phthalimide, 50 g(0.27 mol) of 2-chlorocyclohexanone and 200 ml of dimethylformamide isstirred at 95° C. for 8 hours. The mixture is poured over ice-coldwater, ether is added and the mixture is stirred until crystallizationof 2-phthalimidocyclohexanone is obtained. The product is drained,washed with water and with ether, and dried under vacuum. 40 g of thecompound are obtained (m.p.=155° C.). A mixture of 40 g (0.16 mol) ofthe preceding derivative in 200 ml of acetic acid and 200 ml of 48%hydrobromic acid is then stirred under reflux for 4 hours. The mixtureis cooled on an ice bath, the phthalic acid filtered and the product isconcentrated under vacuum. The evaporation residue is taken up in 100 mlof ethanol and 100 ml of toluene and then concentrated under vacuum.This operation is repeated until a well-crystallized residue isobtained. It is taken up in a 50:50 alcohol/ether mixture filtered anddried under vacuum. 20 g of product are obtained. Yield=64% (m.p.=153°C.).

EXAMPLE 4 1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazol-2-one

A mixture of 1.94 g (0.01 mol) of 2-aminocyclohexanone hydrobromide,1.19 g (0.01 mol) of phenyl isocyanate and 4 ml of pyridine is stirredat 125° C. for 4 hours. Water is added, the mixture is stirred untilcrystallization is obtained, drained, washed with water and dried. Thecompound is purified by flash chromatography on silica, eluting with a95:5 CH₂Cl₂/CH₃OH mixture. 0.7 g of product is recovered. Yield=33%(m.p.=224° C.).

EXAMPLE 5 2-chloro-1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazole

A mixture of 2.3 g (0.0107 mol) of1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazol-2-one and 30 ml of POCl₃ isstirred under reflux for 6 hours. The excess POCl₃ is evaporated undervacuum and the residue is hydrolyzed with water and concentratedammonium hydroxide. The mixture is extracted twice with methylenechloride, evaporated and the residue is purified by flash chromatographyon silica with an 80:20 heptane/ethyl acetate eluent. 0.8 g of productis recovered. Yield=32.2%.

EXAMPLE 6 4,5,6,7-tetrahydro-2H-benzimidazole

400 ml of formamide are added to 50 g (0.377 mol) of2-chlorocyclohexanone placed in a 1-liter three-necked flask and thenthe mixture is heated at 180° C. for 2 h 30 min. The medium, havingreturned to room temperature, is poured over a 1 N sodium hydroxidesolution (380 ml). This medium is then placed in a continuousliquid-liquid extractor and extracted with 400 ml of ethyl acetate for 6h. The organic phase is dried over MgSO₄, concentrated under vacuum andthen purified on a silica column using a gradient (methanol from 5 to10% in dichloromethane). 10.2 g of product are obtained in the form of agum. Yield=22%.

EXAMPLE 7 1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazole

250 mg (2 mmol) of 4,5,6,7-tetrahydrobenzimidazole, 1.1 g (2.5 mmol) oftriphenylbismuth, 363 mg (2 mmol) of copper acetate and 203 mg (2 mmol)of triethylamine are stirred in 5 ml of dichloromethane at roomtemperature for 24 hours. 2 grams of silica are then added and then themedium is concentrated under reduced pressure. The powder obtained isdeposited on a silica gel and the expected product is eluted with adichloromethane/methanol/ammonium hydroxide (95/5/0.5) mixture. 315 mg(79.5%) of 1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazole are obtained.

EXAMPLE 8 1-phenyl-2-methylthio-4,5,6,7-tetrahydro-1H-benzimdazole

2.36 g (12 mmol) of 1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole areplaced in a 100-ml three-necked flask under nitrogen, 20 ml oftetrahydrofuran are added and then the mixture is cooled to −78° C. 9 ml(14.3 mmol) of a 1.6 N butyllithium solution in hexane are then slowlyadded. The mixture is stirred at −80° C. for 5 minutes and then thetemperature is allowed to rise to −20° C. and the mixture is stirred fora further 45 minutes at this temperature. The reaction medium is thencooled to −80° C. and a solution of 2.24 g (24 mmol) of dimethyldisulphide diluted in 10 ml of tetrahydrofuran is introduced into itdropwise. When the addition is complete, the medium is allowed to returnto room temperature. It is then cooled to 0° C. before gentlyintroducing 15 ml of water and then 15 ml of ethyl acetate. The phasesare separated and then the aqueous phase is extracted twice with 10 mlof ethyl acetate. The combined organic phases are washed twice with 10ml of water, once with 5 ml of brine and then dried over MgSO₄ andconcentrated under vacuum. The crude reaction product is purified on asilica gel using, as eluting solution, a methanol gradient from 1 to 2%in dichloromethane. 2.17 g of1-phenyl-2-methylthio-4,5,6,7-tetrahydrobenzimidazole are obtained.Yield=74% (m.p.=112° C.).

EXAMPLE 9 1-phenyl-2-methylsulphonyl-4,5,6,7-tetrahydro-1H-benzimidazole

3.8 g of previously moistened alumina, 7.07 g (11.5 mmol) of oxone and10 ml of chloroform are vigorously stirred. A solution of 0.9 g (3.7mmol) of 1-phenyl-2-methylthio-4,5,6,7-tetrahydro-1H-benzimidazole,solubilized in 10 ml of chloroform, is added to this medium and then thestirring is continued while heating under reflux for 2 hours. Themixture is cooled to 0° C. and then filtered, the solid is rinsed with10 ml of chloroform and 10 ml of a 9/1 THF/CH₃OH mixture. The filtrateis concentrated under reduced pressure and then purified on a silicacolumn with the aid of a 99/1 then 98/2 dichloromethane/methanolmixture. 0.65 g of product is obtained. Yield=62%.

EXAMPLE 101-phenyl-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-4,5,6,7-tetrahydro-1H-benzimidazolefumarate

0.031 g (1.33 mmol) of sodium hydride at 60% and 0.25 g of1-benzyl-4-piperidinemethanol are gradually heated to 70° C. in 0.5 mlof dimethylformamide until the evolution of hydrogen ceases. The mixtureis cooled to 0° C. and 0.23 g (1 mmol) of2-chloro-1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole dissolved in 0.5ml of dimethylformamide is added. The mixture is heated at 100° C. for10 hours, water is added and the compound is extracted with methylenechloride. After concentration, it is purified on silica gel with a97:3:0.3 CH₂Cl₂/CH₃OH/NH₄OH mixture. 0.15 g of a thick oil is recoveredwhich is salified in the fumarate form in alcohol. Yield=19.6%(m.p.=102° C.)

EXAMPLE 111-phenyl-2-(piperidin-4-ylmethoxy)-4,5,6,7-tetrahydro-1H-benzimidazole

0.98 g (2.44 mmol) of1-phenyl-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-4,5,6,7-tetrahydro-1H-benzimidazoleis suspended in 20 ml of methanol and supplemented successively with1.54 g (2.44 mmol) of ammonium formate and 0.75 g of 10% palladium oncarbon. The mixture is heated at boiling temperature for 1 hour,filtered and concentrated under vacuum. The product is taken up in 5 Nsodium hydroxide, extracted with methylene chloride and dried overNa₂SO₄. After concentration, 0.55 g of product is recovered. Yield=72%.

EXAMPLE 121-phenyl-2-[[1-(3-hydroxyphenylmethyl)piperidin-4-yl]methoxy]-4,5,6,7-tetrahydro-1H-benzimidazolefumarate

A mixture of 0.55 g (1.176 mmol) of1-phenyl-2-(piperidin-4-ylmethoxy)-4,5,6,7-tetrahydro-1H-benzimidazoleand 0.12 g (0.88 mmol) of 3-hydroxybenzyl chloride in 6 ml ofdimethylformamide is stirred at 75° C. for 15 hours. It is poured overwater, extracted with methylene chloride, dried over Na₂SO₄ andevaporated to dryness. The expected compound is purified on a silicagel, eluting with a 97:3:0.3 CH₂Cl₂/CH₃OH/NH₄OH mixture. The fumarate isproduced in alcohol. Yield=15% (m.p.=149° C.)

EXAMPLE 13 N-phenyl-N′-propargylurea

25 g (0.45 mol) of propargylamine dissolved in 80 ml of toluene areadded dropwise to a suspension of 50 ml (0.45 mol) of phenyl isocyanatein 160 ml of toluene. The mixture is stirred for 1 h 30 min, theprecipitate is filtered, washed with a small amount of toluene and thendried in a vacuum oven at 40° C. 70.7 g of product are obtained.(m.p.=133° C.).

EXAMPLE 14 1,3-dihydro-5-methyl-1-phenyl-2H-imidazol-2-one

0.8 ml of 5.35 N sodium methoxide is added to a suspension of 10 g(0.062 mol) of N-phenyl-N′-propargylurea in 140 ml of toluene. Themixture is heated at the reflux temperature for 4 hours. The solvent isevaporated and then the solid residue is taken up in acetone. Theproduct precipitates, it is filtered, washed with a small amount ofacetone and dried under vacuum at 50° C. 6 g of product are obtained.(m.p.=207° C.).

EXAMPLE 151-(2-hydroxyphenyl)-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole

2.7 ml of a solution of hydrochloric acid (0.5 N) in isopropanol areslowly added, at 0° C. to a solution of 0.5 g (1.32 mmol) of1-(2-methoxyphenyl)-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-1H-imidazolein 15 ml of dichloromethane. The solvents are removed by evaporation andthen the product is taken up in 15 ml of dichloromethane. The solutionis cooled to −15° C. and 1.05 ml of boron tribromide is slowly added.The reaction medium is stirred for 3 h 30 min while allowing thetemperature to return to 20° C. The reaction mixture is poured over iceand sodium bicarbonate is added until a pH=8 is obtained. Afterseparating upon settling out, the aqueous phase is extracted twice withethyl acetate and the combined organic phases are washed with water andthen with brine. The medium is dried over magnesium sulphate, filteredand concentrated. The expected compound is purified on a silica gel,eluting with a 99:1 to 93:7 CH₂Cl₂/CH₃OH mixture. 0.355 g of product isobtained. (Yield 74%)

EXAMPLE 16 1-(2-methoxyphenyl)-2-methylthio-1H-imidazole

8.8 ml (0.065 mol) of aminoacetaldehyde-diethylacetal diluted in 15 mlof toluene are added, under nitrogen, to a solution of 10 g (0.065 mol)of 2-methoxyphenylisothiocyanate in 105 ml of toluene. The reactionmixture is stirred for 1 h 30 min at room temperature. 2.75 ml (0.030mol) of hydrochloric acid at 35% are added and the mixture is stirredfor 2 hours under reflux. The mixture is concentrated and water is addedand the precipitate is triturated. The product is drained, washed withan ether/n-heptane mixture and dried over P₂O₅ overnight. 8.18 g of1-(2-methoxyphenyl)imidazoline-2-thione are thus obtained.

A solution of 8.1 g (0.039 mol) of this1-(2-methoxyphenyl)imidazoline-2-thione in 88 ml of dimethylformamide isadded dropwise, under nitrogen at 0° C., to a suspension of 1.19 g(0.047 mol) of sodium hydride (95%) in 88 ml of anhydrousdimethylformamide. The reaction mixture is stirred for ¾ h at 0° C. 2.7ml (0.043 mol) of methyl iodide previously diluted in 24 ml ofdimethylformamide are added and the mixture is stirred for 1 hour at 0°C. The reaction mixture is poured over ice, extracted three times withethyl acetate and washed twice with water and then with brine. Theproduct is dried over magnesium sulphate, filtered and concentrated. 8.6g of oil are obtained.

The table which follows illustrates the chemical structures and thephysical properties of some compounds of formula (I) according to theinvention.

TABLE (I)

1) Compounds of formula (I) in which A =

R′₃ = R′₄ = —H, R₅ = phenyl, R₆ = phenyl, R₇ = —H No. R₁ R₂ R₃ R₄ m.p.(°C.) Salt  1 CH₃ CH₃ H H 154 Fumarate  2 —(CH₂)₄— H H 162 Fumarate  3—(CH₂)₄— 2-Cl H 155 Fumarate  4 —(CH₂)₄— H 3-OH 149 Fumarate  5 CH₃ CH₂—CH₃ CH₂— H H 148 Fumarate  6 CH₃ CH₃ H H 119 Fumarate   (CH₂)₂— (CH₂)₂— 7 H H H H 145 Fumarate  8 CH₃ CH₃ 2-Cl H 133 Fumarate  9 —(CH₂)₆— H H142 Fumarate 10 H CH₃ H H 154 Fumarate 11 CH₃ CH₃ 2-CH₃ H 134 Fumarate12 CH₃ CH₃ H 3-OH 138 Fumarate 13 CH₃ CH₃ H 3-NH₂ 150 — 14 CH₃ CH₃CH₂— HH 138 Fumarate 15 CH₃CH₂— CH₃ H H 143 Fumarate 16 H H 4-OCH₃ H 160Fumarate 17 —(CH₂)₃— H H 157 Fumarate 18 H H H 3-OH 129 Fumarate 19 H H4-OH H 140 Fumarate 20 H H 2-CH₃ H 121 Fumarate 21 H H 4-Cl H 179Fumarate 22 (CH₃)₃C— H H H  97 Fumarate 23 CH₃ H H H  98 Fumarate 24 H H2-Cl H  85 Fumarate 25 CH₃ CH₃ H 3-CONH₂  75 Fumarate 26 H H 4-CH₃ H 170Fumarate 27 H H 4-F H 170 Fumarate 28 CH₃ H H 3-OH 128 Fumarate 29CH₃CH₂— H H H 140 Fumarate 30 H H 2-OCH₃ H 132 Fumarate 31 H H 3-CH₃ H137 Fumarate 32 H H 2-OH H 153 Fumarate 33 H H 3-F H 132 Fumarate 34 H H3-OCH₃ H 141 Fumarate 35 CH₃CH₂— H H 3-PH 147 Fumarate 36 H H 3-OH H 108Fumarate 37 CH₃ CH₃ H

131 Dibenzyl L-tartrate 38 H H H 3- 172 Fumarate SO₂NH₂ 39* H H H 3-CH₃129 Fumarate 40* H H H 4-CN 125 Fumarate 41 H H 3-OH 3-OH — — *In thesame manner, the compounds for which R₁, R₂ and R₃ = H and R₄ = 2-CH₃,F, CN or CF₃; or 3-F, CN, OCH₃ or CF₃; or 4-CH₃, F, OCH₃ or CF₃ weresynthesized. 2) Compounds of formula (I) in which A =

R₃ and R′₃ = —H, R₅ = phenyl, R₆ = phenyl, R₇ = —H. No. R₁ R₂ R₄ R′₄m.p.(° C.) Salt 42 CH₃ H 3-OH 4-OH 161 — 43 H H 2-F 5-OH 156 Fumarate 44H H 2-F 5-OCH₃ 149 Fumarate 3) Compounds of formula (I) in which A =

R₄ and R′₄ = H, R₅ = phenyl, R₆ = phenyl, R₇ = —H. No. R₁ R₂ R₃ R′₃m.p.(° C.) Salt 45 H H 3-OCH₃ 5-OCH₃ 155 Fumarate 46 H H 3-OH 5-OH 125Fumarate 47 H H 2-OH 5-OH 132 Fumarate 48 H H 2-OCH₃ 5-OCH₃ 110 Fumarate4) Compounds of formula (I) in which A =

R₅ = pyridine, R₆ = phenyl, R₇ = —H. No. R₁ R₂ R₃ R′₃ R₄ R′₄ R₅ m.p.(°C.) Salt 49 H H H H H H pyridin-3-yl 144 Fumarate 5) Compounds offormula (I) in which A =

R₅ = phenyl, R₇ = —H. No. R₁ R₂ R₃ R′₃ R₄ R′₄ R₆ m.p.(° C.) Salt 50 CH₃CH₃ H H 3-CH₃ H pyridin-2-yl 118 Fumarate 51 CH₃ CH₃ H H H Hpyridin-4-yl 110 Fumarate 52 CH₃ CH₃ H H H H pyridin-2-yl 219 Fumarate53 CH₃ CH₃ H H H H pyridin-3-yl 126 Fumarate 6) Compounds of formula (I)in which A =

R₅ = phenyl, R₆ = phenyl, R₇ = —H. No. R₁ R₂ R₃ R′₃ R₄ R′₄ m.p.(° C.)Salt 54 —(CH₂)₄— H H H H 142 Fumarate 7) Compounds of formula (I) inwhich A =

R₅ = phenyl, R₆ = phenyl, R₇ = —H. No. R₁ R₂ R₃ R′₃ R₄ R′₄ m.p.(° C.)Salt 55 H H H H H H 128 Fumarate 8) Compounds of formula (I) in which A=

R₅ = phenyl, R₆ = phenyl, R₇ = —CH₃. No. R₁ R₂ R₃ R′₃ R₄ R′₄ m.p.(° C.)Salt 56 CH₃ H H H H H 130 Fumarate

The compounds of the invention have been the subject of pharmacologicaltrials which have shown their benefit as therapeutically activesubstances.

They have in particular been tested as regards their inhibitory effectson the binding of [³H]-N-methylscopolamine to the M₃ type humanmuscarinic receptors transfected into CHO cells (Chinese hamster ovariancells) (Buckley et al., Mol. Pharmacol. 35: 469-476, 1989). Membranes ofCHO cells, in solution in a 10 mM TRIS-HCl, 2 mM EDTA buffer, pH 7.2,expressing the subtype of human muscarinic receptor M₃, were provided bythe company Receptor Biology (Baltimore, USA).

10 to 30 μg of membranes were incubated in a phosphate buffer, pH 7.4(Sigma, St Louis, Mo.) in the presence of 0.5 nM [³H]N-methylscopolamine(NEN-Dupont, Les Ulis, France) and of a compound of the invention, in atotal volume of 1 ml. The nonspecificity of the binding was determinedwith 0.5 μM of atropine (Sigma, St Louis, Mo.). The incubation (60 minat 25° C.) was stopped by rapid filtration on Whatmann GF/B filtersusing a Brandel filtration device. The filters were washed three timeswith 4 ml of cold phosphate buffer, dried and the radioactivity wasmeasured by liquid scintillation (Ultima Gold scintillant). Theconcentration of compound shifting the specific binding by 500% (IC₅₀)was used to calculate the Ki values based on the Cheng-Prusoff equation.The efficacy of each product studied is expressed by the negativelogarithm of their Ki (pKi).

The IC₅₀ values for the compounds of the invention in relation to the M₃receptors are between 1 and 350 nM.

The compounds of the invention were also studied for their antagonisteffects on the M₃ receptor-mediated contractions of female rabbitdetrusor. Female rabbits (New Zealand, 3-4 kg; supplier ESD), about 20weeks old, were sacrificed by cervical dislocation and thenexsanguinated. After opening the abdomen, the bladders were removed andplaced rapidly in a Krebs bicarbonate solution having the composition(mM): NaCl: 114; KCl: 4.7; CaCl₂: 2.5; MgSO₄: 1.2; KH₂PO₄: 1.2; NaHCO₃:25; ascorbic acid: 1.1; glucose: 11.7. Propranolol (1 μM), methysergide(1 μM), ondansetron (1 μM) and GR113808 (1 μM) were added to the Krebsin order to inhibit, respectively, the β-adrenergic receptors and thevarious subtypes of serotoninergic receptors 5-HT₁/5-HT₂, 5-HT₃ and5-HT₄. The bladders were cleaned, made fat-free and then each side wascut into two longitudinal pieces about 4 mm wide and 15 mm long. Thetissues were then placed in 20 ml containers thermostatted to 37° C.under carbogen (95% O₂, 5% CO₂) aeration and were subjected to a basaltension of 1 g. The tension was measured by means of isometric gauges(Hugo Sacks, type 351) connected to couplers (Gould) which convert andamplify the responses which are plotted on 4-track potentiometricrecorders (Gould) and connected to a data acquisition system (Jad,Notocord). An equilibration time of about 45 minutes was observed duringwhich the Krebs is replaced and the basal tension rectified.

After an equilibration period of 30 minutes, an initial contraction wasmade with carbachol (1 μM), a potent muscarinic agonist. The tissueswere then thoroughly rinsed and then, after another 30-minuteequilibration period, the tissues were incubated for 30 minutes in thepresence or otherwise of a compound of the invention to be studied(concentration 0.1 or 1 μM) before making a carbacholresponse-concentration series per interval of half a logarithm unit. Theconcentrations producing half the maximum effect (EC₅₀ (μM)) werecalculated for each series (absence or presence of the compound to bestudied), then the power of the compound to shift the carbachol responsecurve was determined by calculating the affinity of the antagonist(apparent pA₂ or pK_(B)) according to the method of Furchgott (Handbookof Experimental Pharmacology, 1972, 283-335).

The pK_(B) values for the compounds of the invention are between 7 and9.5.

The compounds of the invention were also studied in relation to theiraffinity towards the 5-HT₄ receptors in the striatum of guinea pigs,according to the method described by Grossman et al., in Br. J.Pharmacol., 109, 618-624 (1993). 300 to 400 g guinea pigs (Hartley,Charles River) undergo euthanasia and their brains are removed. Thestriata are excised and frozen at −80° C. On the day of the experiment,the tissue is thawed at +4° C. in 33 volumes of 50 mM Hepes-NaOH buffer(pH=7.4 at 20° C.) and homogenized with the aid of a Polytron® mill. Thehomogenate is centrifuged for 10 minutes at 48,000×g, the pellet isrecovered, it is resuspended and it is centrifuged again under the sameconditions. The final pellet is suspended in Hepes-NaOH buffer (30 mg offresh tissue/ml). This membrane suspension is used as it is. 100 μl ofthe membrane suspension is incubated at 0° C. for 120 minutes, in thepresence of 0.1 nM [³H]GR113808 (specific activity: 80-85 Ci/mmol), in afinal volume of 1 ml of Hepes-NaOH buffer (50 mM, pH=7.4), in theabsence or in the presence of the test compound. The incubation isstopped by filtration on Whatman GF/B® filters, previously treated with0.1% polyethyleneamine, each tube is rinsed with 4 ml of buffer at 0° C.and the medium is filtered again. The radioactivity retained on thefilters is measured by liquid scintigraphy. The nonspecific binding isdetermined in the presence of 30 μM serotonin. The specific bindingrepresents 90% of the total radioactivity recovered on the filter. Foreach concentration of compound studied, the percentage of inhibition ofthe specific binding of [³H]GR118808 and then the concentration of thetest compound which inhibits 50% of the specific binding (IC₅₀) aredetermined.

The IC₅₀ values for the compounds of the invention are between 1 and 350nM.

Finally, the compounds of the invention were studied in relation totheir antagonist effects on the 5-HT₄ receptors in the oesophagus ofrats. Male Sprague-Dawley rats weighing 300 to 450 g are used. Afragment of about 1.5 cm of the terminal portion of the oesophagus isremoved rapidly, the muscle layer is removed, the inner muscle mucousmembrane is opened longitudinally, it is mounted in an isolated organcontainer containing a Krebs-Henseleit solution at 32° C., oxygenated bya carbogen stream (95% O₂ and 5% CO₂), and it is connected to anisometric transducer under a basal tension of 0.5 g. The compounds arestudied at a concentration of 1 μM. Their capacity to shift therelaxation introduced by 5-HT (at concentrations of 0.1 nM) of theoesophageal tissue precontracted with 1 μM substance P is measured. Thecompounds of the invention are active in this test.

The results of the biological tests show that the compounds of theinvention are antagonists of the M₃ muscarinic and 5-HT₄ serotoninergicreceptors. They can therefore be used in the treatment of irritablebowel syndrome, memory disorders, obstruction of the airways and bladderinstabilities and in particular urinary urgency incontinence.

The compounds of the invention, in combination with appropriate,pharmaceutically acceptable excipients may be provided in any formsuitable for oral or parenteral administration, such as tablets,sugar-coated tablets, gelatin capsules, capsules, oral or injectablesuspensions or solutions, and may contain doses which allowadministration of 0.1 to 50 mg/kg per day.

What is claimed is:
 1. A compound of formula (I)

in which A represents a saturated or unsaturated heterocycle of formula(B), (D), (E) or (F):

R₁ and R₂ represent, independently of each other, a hydrogen, a C₁₋₆alkyl group, or together form a polymethylene group —(CH₂)_(n)—, itbeing possible for n to take the values from 3 to 6, R₅ represents aphenyl or a 2-, 3- or 4-pyridine, the phenyl or the pyridine beingsubstituted with R₃ and R′₃, wherein R₃ and R′₃ represent, independentlyof each other, a hydrogen atom, a halogen atom, a hydroxyl, a C₁₋₄ alkylor C₁₋₆ alkoxy group, R₆ represents a phenyl or a 2-, 3-, or 4-pyridine,the phenyl or the pyridine being substituted with R₄ and R′₄, wherein R₄and R′₄ represent, independently of each other, a hydrogen atom, ahalogen, a hydroxyl, an amino, a cyano, a sulphonamide, anaminocarbonyl, a trifluoromethyl, a C₁₋₆-alkoxy, (di)hydroxy-C₁₋₆ alkoxyor C₁₋₄ alkyl group, and R₇ represent a hydrogen atom or a C1-2 alkylgroup, in the form of an enantiomer, a diastereoisomer or a mixture ofthese different forms, or an N-oxide thereof and their addition saltswith pharmaceutically acceptable acids.
 2. A compound according to claim1 wherein A represents a piperidine (B) and R₅ represents a phenyl.
 3. Acompound according to claim 1 wherein the compound is chosen from thefollowing compounds:1-phenyl-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole;1-(2-hydroxyphenyl)-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole;1-(3-hydroxyphenyl)-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole;1-phenyl-2-[[1-(3-hydroxyphenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole;1-phenyl-2-[[1-(2-fluoro-5-hydroxyphenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole;1-phenyl-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-4,5-dimethyl-1H-imidazole;1-phenyl-2-[[1-(3-hydroxyphenylmethyl)piperidin-4-yl]methoxy]-4,5-dimethyl-1H-imidazole;1-phenyl-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-4-methyl-1H-imidazole;1-phenyl-2-[[1-(3-hydroxyphenylmethyl)piperidin-4-yl]methoxy]-4-methyl-1H-imidazole;1-phenyl-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-4-ethyl-1H-imidazole;1-phenyl-2-[[1-(3-hydroxyphenylmethyl)piperidin-4-yl]methoxy]-4-ethyl-1H-imidazole;and1-phenyl-2-[[1-(3-hydroxyphenylmethyl)piperidin-4-yl]methoxy]-4,5,6,7-tetrahydro-1H-benzimidazole,in the form of an enantiomer, a diastereoisomer or a mixture of thesedifferent forms, or an N-oxide thereof and their addition salts withpharmaceutically acceptable acids.
 4. A process for the preparation of acompound according to claim 1 wherein a chloroimidazole of formula (VII)

or a sulphone of formula (XI)

is reacted with an alcohol of formula (XIV),

in which A, R₆ and R₇ are as defined in claim
 1. 5. A pharmaceuticalcomposition comprising a compound according to claim 1 and one or morepharmaceutically acceptable excipients.
 6. A pharmaceutical compositioncomprising a compound according to claim 2 and one or morepharmaceutically acceptable excipients.
 7. A pharmaceutical compositioncomprising a compound according to claim 3 and one or morepharmaceutically acceptable excipients.
 8. A method for the treatment ofdiseases in which M₃ muscarinic and/or 5-HT₄ serotoninergic receptorsare involved which comprises administering to a patient in need of suchtreatment an effective amount of a compound according to claim
 1. 9. Amethod for the treatment of diseases in which M₃ muscarinic and/or 5-HT₄serotoninergic receptors are involved which comprises administering to apatient in need of such treatment an effective amount of a compoundaccording to claim
 2. 10. A method for the treatment of diseases inwhich M₃ muscarinic and/or 5-HT₄ serotoninergic receptors are involvedwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 3. 11. A methodaccording to claim 8 for the treatment of irritable bowel syndrome,memory disorders, obstruction of the airways, and bladder instabilities.12. A method according to claim 9 for the treatment of irritable bowelsyndrome, memory disorders, obstruction of the airways, and bladderinstabilities.
 13. A method according to claim 10 for the treatment ofirritable bowel syndrome, memory disorders, obstruction of the airways,and bladder instabilities.
 14. A method according to claim 11 for thetreatment of urinary incontinence.
 15. A method according to claim 12for the treatment of urinary incontinence.
 16. A method according toclaim 13 for the treatment of urinary incontinence.